How should I initiate treatment for major depressive disorder (MDD)?

Treatment Initiation for Major Depressive Disorder

For moderate to severe MDD, initiate a second-generation antidepressant (SSRI or SNRI) at standard starting doses, selected based on adverse effect profile, cost, and patient preference, with close monitoring beginning within 1-2 weeks. 1

Severity-Based Treatment Algorithm

Mild Depression (5-6 symptoms, minimal functional impairment)

• Start with cognitive behavioral therapy (CBT) alone as first-line monotherapy, which achieves equivalent remission rates to antidepressants while avoiding medication side effects 2
• Reserve pharmacotherapy for patients who prefer medication or lack access to CBT 1

Moderate Depression (7-8 symptoms, moderate functional impairment)

• Initiate either CBT or a second-generation antidepressant as monotherapy—both options have comparable effectiveness based on moderate-quality evidence 1, 2
• If choosing pharmacotherapy, select an SSRI (sertraline, escitalopram, citalopram, fluoxetine, or paroxetine) or SNRI (venlafaxine, duloxetine) 1

Severe Depression (≥9 symptoms, severe functional impairment, or high-risk features)

• Begin combination therapy with both an antidepressant AND CBT concurrently—this approach nearly doubles remission rates (57.5% vs 31.0%) compared to medication alone 2, 3
• High-risk features requiring immediate severe classification regardless of symptom count include: specific suicide plan/intent, recent attempt, active psychosis, or first-degree relative with bipolar disorder 2

Specific Pharmacotherapy Initiation

Starting Doses (FDA-Approved)

• Sertraline: 50 mg once daily for MDD 4
• Escitalopram: 10 mg once daily 1
• Fluoxetine, paroxetine, citalopram: 20 mg once daily 1
• Venlafaxine or duloxetine: Standard SNRI starting doses 3

Medication Selection Criteria

No second-generation antidepressant demonstrates superior efficacy over another—selection should be based on: 1

• Adverse effect profile: Bupropion has lower sexual dysfunction rates than SSRIs; paroxetine has higher sexual dysfunction rates than other SSRIs 1
• Cost considerations: Generic SSRIs are typically most affordable 1
• Patient preference and prior response: Previous positive or negative experiences guide selection 1
• Comorbidities: SNRIs may be slightly more effective for severe depression but carry higher nausea/vomiting rates 2

Critical Early Monitoring Protocol

Week 1-2 Assessment (Mandatory)

Assess all patients within 1-2 weeks of treatment initiation for: 1, 2

• Suicidality monitoring: Risk for suicide attempts peaks during the first 1-2 months of treatment; SSRIs increase suicide attempt risk compared to placebo 1
• Emergence of agitation, irritability, or unusual behavioral changes indicating worsening depression 1
• Early adverse effects: Gastrointestinal symptoms, sleep disturbances, sexual dysfunction 5
• Treatment adherence: Up to 50% of MDD patients demonstrate non-adherence 3

Week 6-8 Response Assessment

Modify treatment if inadequate response by 6-8 weeks—response is defined as ≥50% reduction in symptom severity on validated scales (PHQ-9, HAM-D) 1, 2

Options for inadequate response include: 1, 3

• Dose escalation (up to 200 mg/day for most SSRIs) 4
• Switching to a different antidepressant class 3
• Adding CBT to ongoing pharmacotherapy (strongest evidence for augmentation) 3
• Augmentation with bupropion or buspirone 3

Treatment Duration

First Episode

Continue treatment for 4-9 months after achieving satisfactory response to prevent relapse 1, 2

Recurrent Episodes (≥2 prior episodes)

Maintain treatment for ≥1 year or longer—patients with recurrent depression benefit from prolonged maintenance therapy 1, 2, 3

Common Pitfalls to Avoid

• Premature discontinuation: Therapeutic effects typically require 4-6 weeks; do not abandon treatment before adequate trial duration 2
• Inadequate dosing: While standard starting doses are appropriate, some patients may require higher doses for response 6
• Assuming treatment resistance without confirming adherence: Check adherence and plasma levels if uncertain before declaring treatment failure 3
• Failing to address comorbidities: Screen for anxiety disorders (present in majority of MDD patients), substance use disorders, and bipolar spectrum conditions before initiating treatment 5, 2
• Neglecting safety planning: Develop written safety plan limiting access to lethal means and establishing emergency protocols at initial visit 2

Alternative and Complementary Approaches

Do not recommend psychobiotic supplements—no FDA-approved formulations exist and evidence is insufficient 2

For patients preferring non-pharmacological options beyond CBT: 5, 2

• Acupuncture as adjunct to antidepressants: Moderate-certainty evidence shows increased remission rates (35.7% vs 26.1%) when added to ongoing pharmacotherapy 2
• St. John's wort: No significant difference from standard antidepressants in mild-moderate depression, but drug interactions limit use 1, 5
• Supervised aerobic exercise: Comparable remission to sertraline with lower discontinuation rates 2